DESCRIPTION: Varicocele-associated human male infertility (VAI) represents greater then 20 percent of male infertility in the US. Surgical repair of varicocele restores fertility only 1/3 of time. Identification of VAI likely to benefit from surgical correction offers health cost savings. In preliminary studies, VAI patients' seminal plasma and testes biopsies contain significantly higher cadmium (Cd2+) than other infertile males, though blood levels were indistinguishable. VAI sperm lose normal sperm surface proteins binding actin, including mannose and progesterone receptors, and normal sperm head cytoskeletal structures. In vitro incubation of fertile human sperm in Cd2+ containing media replicate VAI cytoskeletal defects. Autometallographic imaging of biopsies confirmed high Cd2+ in VAI testes. Probing serial testes sections revealed decreased actin expression with differentiation stage, and increased frequency of apoptotic nuclei in VAI tubules. Sperm voltage-dependent calcium channels (VDCC) are an apparent entry point for Cd2+ VDCC isoform expression variability correlates with mannose receptor function. VAI patient partners became pregnant within three years only if surgical correction restored normal mannose receptor function. Therefore Cd2+ may be a cofactor with heat in producing VAI. In an expanded prospective study we will determine if seminal Cd2+ correlates with testicular Cd2+, and if seminal Cd2+, testicular Cd2+ and scrotal temperature are biomarkers for VAI reversal assessed by pregnancy and birth, taking one testicular biopsy and duplicate semen samples before and 3 months after correction. Intermediate endpoints for characterizing VAI will include: seminal plasma and testicular Zn2+, testicular Cd2+ and Zn2+ distributions by autometallography, sperm response to capacitating incubation (mannose receptor assay) and to acrosome-reaction induction by polvalent mannose, assessment of actin distributions, levels of apoptosis and VDCC expression. Controls will include men from couples undergoing IVF/ICSI for non-obstructive azoospermia and males with primary VAI who refuse correction. To further characterize VAI, abnormalities in intermediate endpoints among individuals (e.g. apoptosis and actin loss) will be correlated with changes in VDCC primary structure in regions afecting metal ion sensitivity, channel gating potential and Ca2+ channel blocker binding as assesed from VDCC mRNA present in mature sperm, and with changes in a region of VDCC channel precursor sensitive to mannose-induced proteolysis, assessed by Western blot of sperm membrane proteins. Controls will include fertile donors and fertile men with varicocele.